Pharmacokinetic study of a new synthetic MMP inhibitor (Ro 28-2653) after IV and oral administration of cyclodextrin solutions

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Marie PietteG Piel

Abstract

Ro 28-2653 (5-biphenyl-4-yl-5-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione) is a new synthetic inhibitor of matrix metalloproteinases (MMPs) with a high selectivity towards MMP2, MMP9 and membrane type 1-MMP. It has been shown that cyclodextrins (CDs) are able to form inclusion complexes with Ro 28-2653 and to increase its aqueous solubility. The aim of this study is to demonstrate that an increase in Ro 28-2653 solubility, via ternary complex formation, can lead to an increase in the oral bioavailability of this drug. This study shows that a synergistic effect exists between hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and l-lysine. The use of this multicomponent system enabled the preparation of oral and intravenous solutions of Ro 28-2653. In vivo evaluation of the oral solution of the inclusion complex of Ro 28-2653 in comparison with a suspension of the same uncomplexed drug showed a significant (p<0.05) increase in absolute bioavailability. The area under curve (AUC) and the peak serum concentration (Cmax) were approximately 10 times higher than those obtained with the suspension, while the time (Tmax) to reach Cmax was reduced. Moreover, in vivo administration of Ro 28-2653 solutions highlighted some infor...Continue Reading

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Citations

Jul 27, 2012·Therapeutic Delivery·Patricia CallejaJuan M Irache
Jun 13, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Junzuan XiYing Pan
Jul 9, 2008·Drug Development and Industrial Pharmacy·Xiangrong ZhangDafang Zhong
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Jun 11, 2015·The Journal of Pharmacy and Pharmacology·Thorsteinn LoftssonAngel Concheiro
Aug 11, 2021·Pharmaceutics·Virginia AiassaAriana Zoppi

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